Adrenomedullin in the growth modulation and differentiation of acute myeloid leukemia cells.

Adrenomedullin (ADM) is a regulatory peptide endowed with multiple biological effects, including the regulation of blood pressure, cell growth and innate host defence. In the present study, we demonstrated that ADM signaling could be involved in the impaired cellular differentiation of myeloid leukemia cells to mature granulocytes or monocytes by modulating RAMPs/CRLR expression, PI3K/Akt cascade and the ERK/MAPK signaling pathway. When exogenously administered to in vitro cultures of HL60 promyelocytic leukemia cells, ADM was shown to exert a strong proliferative effect with minimal upregulation in the expression level of monocyte antigen CD14. Notably, the experimental inhibition of ADM signaling with inhibitor ADM22-52 promoted a differentiative stimulation towards monocytic and granulocytic lineages. Moreover, based on the expression of CD31 relative to CD38, we hypothesized that an excess of ADM in bone marrow (BM) niche could increase the transendothelial migration of leukemia cells while any inhibitory event of ADM activity could raise cell retention in hyaluronate matrix by upregulating CD38. Taken into consideration the above evidence, we concluded that ADM and ADM22-52 could differently affect the growth of leukemia cells by autocrine/paracrine mechanisms and may have clinical relevance as biological targets for the intervention of tumor progression.

Synthesis of sialoclusters appended to calix[4]arene platforms via multiple azide-alkyne cycloaddition. New inhibitors of hemagglutination and cytopathic effect mediated by BK and influenza A viruses.

Tetra- and octavalent sialoside clusters were prepared in good yields exploiting for the first time the multiple copper-catalyzed cycloaddition of a propargyl thiosialoside with calix[4]arene polyazides. The cycloadducts featured the hydrolytically stable carbon-sulfur bond at the anomeric position and the 1,4-disubstituted triazole ring as the spacer between the sialic acid moieties and the platform. It was demonstrated that these unnatural motifs did not hamper the desired biological activity of the sialoclusters. In fact, they were able to inhibit, at submillimolar concentrations, the hemagglutination and the viral infectivity mediated both by BK and influenza A viruses.